Cysteine proteases, such as cathepsins B, L, S, and O.sub.2, have been implicated in a number of diseases, including cancer metastasis and invasion (Clin. Exp. Metastasis 1992, 10, 145-155; Cancer Metastasis Rev. 1990, 9, 333-352), arthritis (Int. J. Biochem. 1993, 25, 545-550; Arthritis Rheumatism 1994, 37, 236-247; J Rheumatol. 1993, 20, 1176-1183; Biochem. Pharmacol. 1993, 44, 1201-1207), muscular dystrophy (Am. J. Pathol. 1986, 122,193-198; 1987,127, 461-466), myocardial infarction (J. Am. Coll. Cardiol. 1983, 2, 681-688), bacterial infection (Rev. Infect. Dis., 1983, 5, 5914-5921) and common cold (Biochem. 1995, 34, 8172-8179). The calcium-associated cysteine proteases calpains I and II have been associated with ischemia and hypoxia, Alzheimer's disease (Proc. Natl. Acad. Sci. U.S.A. 1993, 90, 2628-2632) and cataracts (J. Biol. Chem. 1993, 268, 1937-1940). These medical disorders are thought to be due, among other factors, to the deregulation of the above mentioned cysteine proteases class of enzymes. Therefore this class of enzymes is excellent targets for the development of specific inhibitors as possible therapeutic agents.
Several types of cysteine proteases inhibitors have been reported, such as peptide aldehydes (Biochim. Biophys. Acta 1991, 1073-43), nitrites (Biochim. Biophys.Acta 1990, 1035, 62-70), halomethyl ketones (Anal. Biochem. 1985, 149, 461-465; Acta. Biol. Med. Ger. 1981, 40, 1503-1511; Biochem. Phar. 1992, 44, 1201-1207), diazomethyl ketones (Biochem. J. 1988, 253, 751), acyloxy methyl ketones (J. Med. Chem. 1994, 37, 1833-1840; J. Am. Chem. Soc. 1988,110, 4429-4431), ketomethylsulfonium salt (J. Biol. Chem. 1988, 263, 2768-2772), .alpha.-ketocarbonyl compounds (J. Med. Chem. 1993, 36, 3472-3480; 1994, 37, 2918-2929), vinyl sulfones (J. Med. Chem. 1995, 38, 3193-3196), monobactam derivatives (U.S. patent application Ser. No. 08/1415055, 1995) and epoxysuccinyl derivatives (Agric. Biol. Chem. 1978, 42, 523-527). These inhibitors, in general, have a peptidyl affinity group and a group reactive towards the thiol of the cysteine residue in cysteine proteases. Some of them are clinically useful. However, the efficacy in vivo is not as much as expected on the basis of in vitro inhibitory activity and may be due to lower selectivity towards other proteases and poor pharmacokinetics. There exists a continuing need to develop new cysteine proteases inhibitors with high selectivity, lower toxicity and better pharmacokinetics.
In continuation of our efforts to find out the low molecular weight cysteine protease inhibitors for therapeutic uses, we have focused our attention at 6-substituted oxapenam derivatives on the basis of the molecular modeling studies of 3-substituted-4-oxa-1-azabicyclo 3,2,0! heptan-7-one derivatives.